Project Summary Vascular cognitive impairment (VCI) is the second most common cause of dementia after Alzheimer's disease (AD). The mechanisms underlying VCI are poorly understood, with no specific therapy currently exists to prevent or treat VCI. We have previously observed increased expression and activity of the enzyme soluble epoxide hydrolase (sEH) in microvascular endothelium of human brain tissue from deceased patients with pre-mortem VCI. We have also observed in mice that high-fat diet (HFD)-induced type 2 diabetes causes a similar increase in cerebrovascular sEH. Our preliminary data demonstrate that transgenic mice with constitutive overexpression of human sEH in endothelium (Tie2-hsEH) have impaired spatial memory (Morris Water Maze), suggesting that endothelial sEH is causally linked to cognitive impairment. Proposed studies will determine if endothelial sEH upregulation impairs cognition by a neuro-inflammatory mechanism mediated by infiltration of brain tissue by monocyte-derived macrophages. Studies will also determine if mice with endothelial-specific deletion of sEH (Tie2-Cre/floxed-sEH) are protected from HFD-induced neuronal loss, neuroinflammation and cognitive impairment. Finally, we will use two different therapies, one aimed at inhibiting sEH and one aimed at preventing monocyte/macrophage infiltration, to determine if these agents can prevent (when given prior to cognitive decline) or reverse (when given after cognitive impairment) the age-related cognitive deficit in Tie2-hsEH mice and wild-type mice on HFD.